Oral squamous cell carcinoma is a significant global health problem, comprising one of the ten most common cancers, worldwide. Over the past decade, there has been increased interest in viruses as etiologic agents for cancers of all types. Human papillomavirus (HPV) is the leading candidate for a role as a viral co-factor in oral cancer. In women, estrogen has been linked to multiple malignancies, including breast, cervical and uterine cancers, but, heretofore, estrogen has not been studied as a possible factor in oral cancer, despite the fact that well-recognized hyperplastic lesions of the oral cavity occur as a result of hormonal changes during pregnancy and puberty. We hypothesize that HPV and estrogen interact in the oral cavity to cause proliferative verrucous leukoplakia, an oral condition, seen predominantly in women, which is associated with a high prevalence of HPV infection and which ultimately eventuates in oral cancer. Interactions between HPV and estrogen in the pathogenesis of cervical cancer have been studied in a specific transgenic mouse model (K14-HPV16), in which a portion of the HPV16 genome is targeted to the progenitor compartment of the epithelium; by means of the keratin 14 promoter. Preliminary data on the oral cavity in this model strongly support its value for studies of the interactions between these two agents at this site as well. To that end, our specific aims are: 1) to determine whether estrogen can promote transformation of the oral epithelium to a premalignant or malignant phenotype in the K14-HPV16 transgenic mouse model, 2) to perform a prospective analysis of changes in biomarkers associated with proliferation and transformation in the oral epithelium of K14-HPV16 mice that have been exposed to estrogen in a longitudinal manner, and 3) to analyze changes in biomarkers in human specimens of proliferative verrucous leukoplakia to determine correlations with the mouse model. The proposed study is unique in that it addresses the question of estrogen and viral interaction as a possible etiology of oral cancer, an important issue which has not ever been investigated. We feel strongly that this knowledge will ultimately result in appropriate timing of specific interventional therapies and preventive strategies for proliferative verrucous leukoplakia and oral cancer in the future, and will address an oral health problem that is a significant women's health issue.